This invention relates to processes for the preparation of 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-2,3,4,5- tetrahydro-1H-pyrido[4,3-b]indole (flutroline), a neuroleptic agent having valuable therapeutic activity, see Plattner et al., U.S. Pat. No. 4,001,263, and Herbert et al., J. Med. Chem. 23, pages 635-643.
Plattner et al. and Harbert et al. also describe the earliest synthesis of flutroline: p-fluorophenylhydrazine is condensed with N-carbethoxy-4-piperidone to form 8-fluoro-2-carbethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. By the Ullman reaction the latter is arylated to form the 5-(p-fluorophenyl) derivative and then hydrolyzed under vigorous basic conditions to yield 8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (an intermediate common to the present processes). The earlier synthesis of flutroline is completed by 2-alkylation with 3-(p-fluorobenzoyl)propyl chloride and reduction of the ketone to an alcohol group with sodium borohydride.
Welch, U.S. Pat. No. 4,014,890, has described an alternative synthesis of the same earlier intermediate 8-fluoro-5-(p-fluorophenyl)-2-carbethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3- b]indole, viz., condensation of 1,1-di(p-fluorophenyl)hydrazine with N-carbethoxy-4-piperidine.
Massett, U.S. patent application Ser. No. 425,151, filed Sept. 30, 1982 discloses a superior process for the preparation of the earlier and present intermediate 8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, alternatively referred to herein as R-H. Massett's process is also specifically disclosed below.
Welch, U.S. patent application Ser. No. 334,195, filed Dec. 24, 1981, describes preparation of flutroline by reductive alkylation of R-H with 2-hydroxy-5-(p-fluorophenyl)tetrahydrofuran. Welch, U.S. patent application Ser. No. 331,494, filed Dec. 17, 1981, describes preparation of flutroline by condensation of R-H with formaldehyde and p-(1-hydroxy-2-propynyl)phenyl fluoride, followed by hydrogenation of the resulting 2-[4-p-fluorophenyl)-4-hydroxy-2-butynyl] intermediate.
The present 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-indoles are alternatively named as 1,2,3,4-tetrahydro-gamma-carbolines. In either case, numbering is as exemplified in the formula for the radical R, which is defined herein as: ##STR1##